BCL11A microRNAs for treating hemoglobinopathies
Inventors
Williams, David A. • GUDA, Swaroopa
Assignees
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Publication Number
US-12350284-B2
Publication Date
2025-07-08
Expiration Date
Abstract
Embodiments herein provide specially designed synthetic BCL11A-targeting microRNAs for RNA polymerase II expression, and methods of use to treat hemoglobinopathies, such as sickle cell disease or thalassemia, by increasing the expression levels of fetal hemoglobin levels.
Core Innovation
The disclosure describes gene therapy for hemoglobinopathies by selectively knocking down BCL11A to derepress γ-globin and increase fetal hemoglobin (HbF). It addresses sickle cell disease (SCD) and thalassemia, including β-thalassemia, through increasing HbF levels associated with regulation of hemoglobin expression.
A synthetic BCL11A microRNA comprises a first BCL11A segment, a loop segment derived from miRNA144, and a second BCL11A segment arranged in tandem in a 5′ to 3′ direction. The loop segment is between and directly linked to the first and second BCL11A segments, and the second BCL11A segment is complementary to the first BCL11A segment so that the first and second BCL11A segments base pair to form a hairpin loop.
The disclosure further specifies sequence constraints in which the first BCL11A segment starts with a -GCGC- at the 5′ end and the second BCL11A segment ends with a -GCGC- at the 3′ end. The loop segment is specified as AGTTTGCGATGAGAC or AGTTTGCGATGAGACAC (SEQ ID NO: 68), and the nucleic acid embodiments include a synthetic BCL11A microRNA having a complete nucleotide sequence, including SEQ ID NO: 98.
The document further describes isolated nucleic acid molecules comprising SEQ ID NO: 98, including vectors and isolated host cells that contain the nucleic acid, and delivery contexts including lentiviral self-inactivating vectors, RNA polymerase II expression, hematopoietic stem/progenitor cells, and an erythroid lineage.
Claims Coverage
The claim coverage includes two independent features: one directed to a synthetic BCL11A microRNA architecture and one directed to an isolated nucleic acid molecule comprising SEQ ID NO: 98.
Synthetic BCL11A microRNA architecture with miRNA144-derived loop
A synthetic BCL11A microRNA comprising a first BCL11A segment, a loop segment derived from miRNA144, and a second BCL11A segment arranged in tandem in a 5′ to 3′ direction, where the loop segment is between and directly linked to the first and second BCL11A segments, the second BCL11A segment is complementary to the first BCL11A segment to form a hairpin loop, and the loop segment consists of AGTTTGCGATGAGAC or AGTTTGCGATGAGACAC (SEQ ID NO: 68), with the first BCL11A segment starting with -GCGC- at the 5′ end and the second BCL11A segment ending with -GCGC- at the 3′ end.
Isolated nucleic acid comprising SEQ ID NO: 98
An isolated nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 98.
Overall, the claims protect the specific synthetic BCL11A microRNA design with tandem complementary BCL11A segments and a miRNA144-derived loop, together with the isolated nucleic acid defined by SEQ ID NO: 98.
Stated Advantages
BCL11A expression inhibition is stated as the basis for the approach.
Increases fetal hemoglobin (HbF) by derepressing γ-globin via BCL11A knockdown.
Provides gene therapy applicable to hemoglobinopathies including sickle cell disease (SCD) and thalassemia, including β-thalassemia.
Documented Applications
Gene therapy use cases for hemoglobinopathies, including genetically modified hematopoietic cells transduced with lentiviral vectors carrying defined BCL11A-targeting nucleotide sequences or a synthetic BCL11A microRNA.
Treatment settings described for hemoglobinopathy contexts that include sickle cell disease and thalassemia.
Gene therapy for hemoglobinopathies including sickle cell disease (SCD) and thalassemia, including β-thalassemia, by BCL11A knockdown to increase HbF.
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